title: Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment.
abstract: Classical proinflammatory eicosanoids, and more recently discovered lipid mediators with anti-inflammatory and proresolving bioactivity, exert a complex role in the initiation, control, and resolution of inflammation. Using a targeted lipidomics approach, we investigated circulating lipid mediator responses to resistance exercise and treatment with the NSAID ibuprofen. Human subjects undertook a single bout of unaccustomed resistance exercise (80% of one repetition maximum) following oral ingestion of ibuprofen (400 mg) or placebo control. Venous blood was collected during early recovery (0-3 h and 24 h postexercise), and serum lipid mediator composition was analyzed by LC-MS-based targeted lipidomics. Postexercise recovery was characterized by elevated levels of cyclooxygenase (COX)-1 and 2-derived prostanoids (TXB2, PGE2, PGD2, PGF2α, and PGI2), lipooxygenase (5-LOX, 12-LOX, and 15-LOX)-derived hydroxyeicosatetraenoic acids (HETEs), and leukotrienes (e.g., LTB4), and epoxygenase (CYP)-derived epoxy/dihydroxy eicosatrienoic acids (EpETrEs/DiHETrEs). Additionally, we detected elevated levels of bioactive lipid mediators with anti-inflammatory and proresolving properties, including arachidonic acid-derived lipoxins (LXA4 and LXB4), and the EPA (E-series) and DHA (D-series)-derived resolvins (RvD1 and RvE1), and protectins (PD1 isomer 10S, 17S-diHDoHE). Ibuprofen treatment blocked exercise-induced increases in COX-1 and COX-2-derived prostanoids but also resulted in off-target reductions in leukotriene biosynthesis, and a diminished proresolving lipid mediator response. CYP pathway product metabolism was also altered by ibuprofen treatment, as indicated by elevated postexercise serum 5,6-DiHETrE and 8,9-DiHETrE only in those receiving ibuprofen. These findings characterize the blood inflammatory lipid mediator response to unaccustomed resistance exercise in humans and show that acute proinflammatory signals are mechanistically linked to the induction of a biological active inflammatory resolution program, regulated by proresolving lipid mediators during postexercise recovery.
authors.affiliation: School of Exercise and Nutrition Science, Deakin University, Melbourne, Victoria, Australia;
authors.forename: James F
authors.initials: JF
authors.lastname: Markworth
authors.forename: Luke
authors.initials: L
authors.lastname: Vella
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Lingard
authors.forename: Dedreia L
authors.initials: DL
authors.lastname: Tull
authors.forename: Thusitha W
authors.initials: TW
authors.lastname: Rupasinghe
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sinclair
authors.forename: Krishna Rao
authors.initials: KR
authors.lastname: Maddipati
authors.forename: David
authors.initials: D
authors.lastname: Cameron-Smith
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004351:Drug Resistance; D015777:Eicosanoids / Q000378:metabolism; D015444:Exercise / Q000502:physiology*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D015777:Eicosanoids; D005231:Fatty Acids, Unsaturated; D007052:Ibuprofen
keywords: eicosanoid; exercise; inflammation; nonsteroidal anti-inflammatory drug; resolution